1. Field of the Invention
This invention relates to methods of treating mammals to alleviate the symptoms of parkinsonism. This invention also provides compositions useful in such method.
2. Background of the Art
Parkinson's disease is a prevalent, serious neurological disease that afflicts approximately one-half million persons in the United States alone and more than 90 percent of the time the disease becomes manifest after the age of 55. There is no clear evidence that Parkinson's disease is determined by genetic factors and research is underway to discover possible environmental causes, such as infections or toxins.
Administration of one toxin, MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), causes a syndrome that resembles Parkinson's disease when administered to primates. The MPTP-induced parkinsonism syndrome is similar to the idiopathic disease, both pathologically and biochemically, and it responds favorably to the administration of levo-dopa.
Toxic substances like MPTP may be widespread in the environment and there is concern that the accumulated effect of such toxins together with the effects of aging will contribute to development of parkinsonism. (Blume, E., "Street Drugs Yield Parkinson's model, JAMA, 1983, 250, 1314.)
Certain drugs which present the action of dopamine in the basal ganglia of the brain produce a parkinsonism-like syndrome as a side effect. For example, antipsychotic drugs such as the phenothiazines and butyrophenones block postsynaptic receptors for dopamine and cause symptoms that resemble parkinsonism. On the other hand, reserpine produces a parkinsonism-like condition by depleting dopamine available for release by the presynaptic neuron. Certain rare disorders, such as carbon monoxide or manganese poisoning, Wilson's disease and Shy-Drager syndrome, exhibit a parkinsonism-like syndrome as one aspect of a more widespread cerebral disorder.
Whatever its etiology, Parkinson's disease appears late in life and is characterized by loss of smooth control of voluntary muscles. Smooth control of voluntary movements is usually attributed to a balance of two neurotransmitters in the striatal tracts of the basal ganglia--dopaminergic components for inhibitory function, and cholinergic components for excitatory function. Imbalance in these individual systems produces disorders of movement and the disabilities of movement in parkinsonism are attributed to a deficiency in the dopaminergic component caused by the loss of neurons in the basal ganglia. By contrast the hyperkinesis characteristic of Huntington's chorea is thought to result from excessive dopaminergic activity in the basal ganglia. (Calne, D. B. "Parkinsonism, Clinical and Neuropharmacologic Aspects," Postgrad. Med., 1978, 64, 82-88.)
Consequently, the goal of treatment fo parkinsonism is to balance striatal activity by reducing cholinergic activity or to augment dopaminergic function with centrally-active drugs levodopa or L-3,4-dihydroxyphenylalanine.
At present, for example, the most effective treatment of parkinsonism is achieved by levodopa, however many patients experience undesirable side effects such as nausea, vomiting, cardiac arrhythmias, abnormal involuntary movements and psychiatric disturbances. Therefore, there is a continuing search to find useful analogs of dopamine for the treatment of Parkinson's disease or the syndrome known as parkinsonism. Two known classes of dopamine analogs are the aporphines and the ergolines, and the need exists for novel and improved dopaminergic analogues capable of use in treating the symptoms of parkinsonism.